ES2562770T3 - Process for the production of [2- (4-fluoro-benzyl) -phenyl] -acetic acid - Google Patents

Abstract

Process for the production of [2-(4-fluoro-benzyl)-phenyl]-acetic acid, comprising the subsequent steps a) to e): a) reacting phthalic acid anhydride with fluorobenzene in a Friedel reaction Crafts using fluorobenzene itself as the solvent and aluminum chloride as the Lewis acid at reflux temperature, where aluminum chloride is used in a molar ratio to acid anhydride that is >2:1 ; b) by reducing the product obtained in step a) together with the ketone moiety using hydrogen gas, optionally in the presence of a Pd/C catalyst, and using isopropanol (iPrOH) as the solvent; c) reducing the product obtained in step b) with 2.3 equivalents of sodium dihydro-bis (2-methoxy-ethoxy) aluminate (Red-Al) to form the corresponding alcohol; d) chlorinating the alcohol obtained in step c) using an aqueous hydrochloric acid as the chlorinating agent, at 90 ºC in a closed container, and e) inserting CO into the product obtained in step d) by means of an appropriate catalytic system containing Pd, by reacting with CO in a mixture of THF and H2O in the presence of a) sodium acetate, K2C03 or Et3N and b) triphenylphosphine.

Description

DESCRIPTION

Procedure for the production of [2- (4-fluoro-benzyl) -phenyl] -acetic acid

The present invention to a new process for the production of [2- (4-fluoro-benzyl) -phenyl] -acetic acid, a compound that is obtainable from the phthalic acid anhydride.

This derivative is an important intermediate compound in the synthesis of a series of compounds, which are disclosed in the international patent application document WO 97/38991, which has the general formula (A) wherein R1 and R1 are inter alia hydrogen and / or methyl, R3 and R4 are hydrogen or halogen, X is CH2, O or S, n is 1 and p and q are 0, 1 or 2.

image 1

The compounds according to Formula (A) were found to be useful for the treatment and / or prevention of 10 central nervous system (CNS) disorders, cardiovascular disorders and gastrointestinal disorders. Its synthesis has been described, among other references, in WO03 / 048146 and WO03 / 048147. In these last documents (see Scheme 1), it has been disclosed that [2- (4-fluoro-benzyl) -phenyl] -acetic acid according to Formula (I) can be prepared by adapting a sequence of operations which is known in the specialty (by French Patent Document No. 4395M, dated October 10, 1966; Can. J. Chem., 1971,49, 74615 754), beginning with an acylation reaction according to Friedel-Crafts using fluorobenzene and the anhydride of

phthalic acid to form a keto-acid according to Formula (IV), followed by a removal by reduction of the ketone group and a homologation of the carboxylic acid function.

Scheme 1

image2

20 The problem that arises with this reaction scheme is that several stages of the synthesis suffer from various disadvantages: environmentally friendly solvents are needed, low performance is achieved and the use of reactant complexes is required or formation of unwanted salt mixtures, such as, for example, Et3NH + Cl \

The objective of the present invention is to provide a process for the production of [2- (4-fluoro-benzyl) -25 phenyl] -acetic acid, which is suitable for carrying out in reactors on an industrial scale (eg more clean and more efficient).

Another object of the present invention is to provide a process in which the [2- (4-fluoro-benzyl) -phenyl] -acetic acid is obtained as a crystalline material with a purity> 95%.

Very surprisingly, the authors of the invention have found that the disadvantages of the known methods can be overcome by a method comprising the subsequent steps a) to e):

a) reacting the phthalic acid anhydride with the fluorobenzene in a Friedel Crafts reaction using the fluorobenzene itself as the solvent and the aluminum chloride as the Lewis acid at the reflux temperature, in which the chloride of aluminum in a molar ratio with respect to the acid anhydride which is> 2: 1;

5

10

fifteen

twenty

25

30

35

40

Four. Five

b) by reducing the product obtained in step a) together with the rest of the ketone using hydrogen gas, optionally in the presence of a Pd / C catalyst, and using isopropanol (iPrOH) as the solvent;

c) reduce the product obtained in step b) with 2.3 equivalents of sodium dihydro-bis (2-methoxy-ethoxy) aluminate (Red-Al) to form the corresponding alcohol;

d) chlorinate the alcohol obtained in step c) using an aqueous hydrochloric acid as the chlorinating agent, at 90 ° C in a closed container, and

e) insert CO into the product obtained in step d) by means of an appropriate catalytic system containing Pd, reacting with CO in a mixture of THF (tetrahydrofuran) and water in the presence of a) sodium acetate, K2C03 or Et3N and b) triphenylphosphine.

A similar step e) of the reaction itself is described in European patent application document EP 1 207 148 A1 (Clariant GmbH, May 22, 2002).

The process according to the invention can be described schematically as follows (see Scheme 2):

Scheme 2

image3

In step a) a Friedel Crafts reaction is used using the chlorobenzene itself as the solvent and aluminum chloride as the Lewis acid for the Friedel-Crafts reaction. Aluminum chloride is used in a molar ratio with respect to phthalic acid anhydride which is> 2: 1. The use of less aluminum chloride leads to incomplete conversion. Preferably, in step a), the reaction is carried out at the reflux temperature of the fluorobenzene, which is 75-80 ° C. When the reaction is carried out at a lower temperature, the reaction rate decreases. Preferably, the reaction mixture obtained in step a), which includes a certain number of aluminum salts, is hydrolyzed with an aqueous hydrochloric acid.

In step b), the reaction is carried out using gaseous hydrogen, optionally in the presence of a Pd / C catalyst and using isopropanol (iPrOH) as the solvent. The use of methanol (MeOH) instead leads to a decreased reaction rate. The use of water leads to the formation of impurities. Preferably, in step b), the reaction is carried out at a temperature above 45 ° C. Below 45 ° C, the reaction is too slow.

In step c), 2.3 equivalents of sodium dihydro-bis (2-methoxy-ethoxy) aluminate ("RedAl") are used. The use of less of the reducing agent could lead to a lower conversion. Preferably, in step c), toluene is used as the solvent. Toluene is the solvent in which commercial sodium dihydro-bis (2-methoxetox) aluminate ("RedAl") is dissolved. Due to the reactive nature of this reducing agent, it is not possible to use protic solvents. Moreover, it is not necessary to isolate the product obtained in step (c) after a treatment, since the toluene solution, which comprises the product, is used as is

In step d) an aqueous hydrochloric acid is used as the chlorinating agent. In step d), the reaction is carried out at 90 ° C. The reaction rate is lower at a lower temperature. In step d), the reaction is carried out in a closed vessel (a pressure accumulation is generated up to 151,987 MPa (1.5 atmospheres)). In an open container, the hydrochloric acid is partially released.

In step e), the product obtained from step d) is reacted with CO within a mixture of THF and H2O, preferably in a 1: 1 ratio, using a catalytic system containing Pd. Water is necessary to carry out the hydrolysis of the complex compound with intermediate palladium. Its combination with THF provides the highest conversion. As a catalytic system for this stage of the reaction, sodium acetate is preferably used. If sodium acetate is omitted, hardly any reaction takes place. Other systems include potassium carbonate or triethylamine. In step e), the reaction is performed using triphenylphosphine (Pt ^ P) as a ligand for palladium. Other ligands have been tested, but the results are not better. Ph3P is the most common compound and is preferably used. Preferably in step e) the reaction is carried out at a pressure of 0.4 MPa (4 bar). At atmospheric pressure, the reaction is very slow. From

3

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

55

preferably, in step e) the reaction is carried out at a temperature of 80 ° C. At a lower temperature, the reaction is slower.

The process according to the invention will now be explained using the following examples.

Experimental part

All materials were purchased from commercial suppliers and used without further purification. The reactions were carried out under a hydrogen atmosphere, when necessary. Only glass containers were used in the laboratory, steel and glass-coated containers are used in the experimental installation. For each reaction, a sample of the reaction mixture is collected and analyzed by means of an HPLC (high performance liquid phase chromatography).

Example

Stage a) [2- (4-Fluoro-benzoM) -benzoic acid (Compound IV)

1. A solution of p-fluorobenzene magnesium bromide (1.2 M solution in THF, 1 eq.) Is added to a 0.4 M solution of phthalic acid anhydride in THF, so that the temperature remains below 30 ° C. After 1 hour, half of the solvent is distilled off and the reaction mixture is stirred overnight at room temperature. The precipitate obtained is filtered off and collected in water (0.3 l / mol). Toluene (1 l / mol) and HClcp are added so that the temperature remains below 35 ° C. After stirring for 1 hour, the organic layer is evaporated (at 50 ° C, in vacuum) and the solid material obtained is dried at 50 ° C under vacuum. Active yield: 69%.

2. Alternatively, a Friedel-Crafts reaction can be performed. In an inertized flask, containing phthalic antidrido, fluorobenzene (1.8 l / mol) is added, followed by a careful addition of aluminum chloride (2.1 eq.). The reaction mixture is heated to 75 ° C (HCl evolution is observed). After 3 hours at 75 ° C, water is added, (1 l / mol). The organic layer is separated and concentrated hydrochloric acid (0.1 l / mol) is added. The fluorobenzene is distilled off and the mixture is cooled to 10 ° C. The precipitate is filtered off, washed with water and dried at 65-70 ° C. Active yield: 85%.

N.B. The fluorobenzene can be recovered by washing with an alkaline solution and discarding the aqueous layer.

Stage b) [2- (4-Fluoro-benzyl) -benzoic acid (Compound V)

In a hydrogenation flask were added 2- (4-fluoro-benzoM) -benzoic acid, monomethyl ether of propylene glycol (1 l / mol) and wet 10% Pd / C (15 g / mol). The hydrogenation was carried out at 50 ° C for 18 hours. Thiophene (0.3 kg / mol) was added and the catalyst was filtered off. The filtrate was heated to 80 ° C and water (1.12 l / mol) was added at that temperature. The mixture was heated to reflux, then cooled to 25 ° C and stirred at that temperature for 1 hour. The precipitate was filtered off, washed with water (1 l / mol) and dried at 50 ° C for 18 hours. Active yield: 83%.

Stage c) [2- (4-Fluoro-benzyl) -phenyl-methanol (Compound VI)

In an inertized flask, containing 2- (4-fluoro-benzyl) -benzoic acid (1 eq.), Toluene (0.8 l / mol) is added and the vessel is cooled to 0-5 ° C. Sodium dihydro-bis (2-methoxy-ethoxy) aluminate ("RedAl") is added dropwise. (1 M in toluene, 2.3 eq.) And the reaction mixture is stirred at 5 ° C for 16 hours. Acetone (3 eq.) Is added dropwise at 5 ° C and the mixture is stirred for 15 minutes. The temperature is allowed to rise to 25 ° C. A solution of sodium hydroxide (5 eq.) Is added and the mixture is stirred vigorously for 20 minutes. The organic layer is separated and washed again with a slightly acidic aqueous solution. The organic layer is filtered over Dicalite and used later in the next stage.

Stage d) [2- (4-Fluoro-benzyl) -phenyl-chloromethane (Compound VII)

In an inertized container, containing a solution of [2- (4-fluoro-benzyl) -phenyl-methanol in toluene, HClcp (5 eq.) Is added, the container is closed and the mixture is stirred at 90 ° C ( a pressure of 0.154 MPa (1.54 bar) is developed). After 6 hours at 90 ° C, the mixture is cooled to 25 ° C and the container is opened. The layers are separated, the organic layer is washed with water and then with a slightly alkaline solution, and is subsequently used in the next stage.

Stage e) [2- (4-Fluoro-benzyl) -phenyl-acetic acid (Compound I)

[2- (4-Fluoro-benzyl) -phenyl] -chloromethane (1 eq.), THF (1 l / mol), water (0.7 l / mol), Pd (OAc) 2 ( 1.3 mol%), dppp (2.6 mol%) and sodium acetate inside an inertized reactor. The reaction mixture is placed under a CO pressure of 0.4 MPa (4 bar) and allowed to stir at 80 ° C for 20 hours. The organic layer separates and evaporates under pressure. Toluene (0.75 l / mol) is added to the residue and the carboxylic acid is extracted with a 2 N solution of sodium hydroxide (0.75 l / mol). The black palladium particles are removed by filtration over Celite. The aqueous layer is placed inside a flask and acetic acid (0.9 l / mol) is added. The mixture is heated to 80 ° C and then allowed to cool spontaneously. Crystallization begins at around 50 ° C. The crystals are filtered off at room temperature, washed with water and dried to form the acid

[2- (4-Fluoro-benzyl) -phenyl] -acetic acid (91%) black. The treatment with organic carbon of 5 g of the black [2- (4- fluoro-benzyl) -phenyl] -acetic acid in 25 ml of a mixture of acetic acid and water (7/3) allows the isolation of crystals pure white [2- (4-fluoro-benzyl) -phenyl] -acetic acid. This stage can be performed before the first addition of acetic acid.

5 Each of the stages has been optimized in the laboratory and then successfully scaled up in the experimental facility.

Claims (3)

10 fifteen twenty the subsequent from Friedel Crafts as the acid of Lewis at the reflux temperature, in which aluminum chloride is used in a molar ratio with respect to the acid anhydride which is> 2: 1; b) by reducing the product obtained in step a) together with the rest of the ketone using hydrogen gas, optionally in the presence of a Pd / C catalyst, and using isopropanol (iPrOH) as the solvent; c) reduce the product obtained in step b) with 2.3 equivalents of sodium dihydro-bis (2-methoxy-ethoxy) aluminate (Red-Al) to form the corresponding alcohol; d) chlorinate the alcohol obtained in step c) using an aqueous hydrochloric acid as the chlorinating agent, at 90 ° C in a closed container, and e) insert CO into the product obtained in step d) by means of an appropriate catalytic system containing Pd, reacting with CO in a mixture of THF and H2O in the presence of a) sodium acetate, K2CO3 or Et3N and b) triphenylphosphine 2. The process according to claim 1, wherein in step e) CO is introduced into the product obtained in step d) by means of an appropriate catalytic system containing Pd reacting with CO in a mixture of THF and H2O in the presence of sodium acetate and triphenylphosphine. 3. The process according to claim 1, wherein in step e) the mixture of THF and H2O is present in a 1: 1 ratio. 1. Process for the production of [2- (4-fluoro-benzyl) -phenyl] -acetic acid, comprising steps a) to e): a) reacting the anhydride of phthalic acid with the fluorobenzene in a reaction using the fluorobenzene itself as the solvent and the aluminum chloride